Myopia (short or near-sightedness) is an eye condition where distant objects cannot be seen clearly. It can be optically corrected (not cured) with spectacles, contact lenses or refractive surgery. Myopia affects many children as they enter school-age, and is becoming a major public health issue. The worldwide growing prevalence seems to be associated with increasing educational pressures, life-style changes involving more near work, and a reduction in the time that children spend outdoors. It is estimated that the current number of 1.45 billion people with the condition will grow to a staggering 2.5 billion by 2020. The rate of myopia has doubled in the US since the 1970s to almost half of teenagers, and the number of high myopes has risen eightfold. In Taiwan and Singapore, the prevalence of myopia is 20%-30% among 6-7-year olds and as high as 84% in high-school students in Taiwan.
The onset of myopia at an early age brings with it the likelihood of life-long eye care, and affects quality of life, education and learning, both when left undetected and in between periodic corrective prescription updates for this continually progressive condition. Myopia also doubles the risk of serious ocular health problems such as glaucoma, and retinal trauma, malfunction and detachment, which can lead to vision loss and blindness. Early onset of myopia in childhood is associated with a higher rate of progression and high myopia in adult life, and we can expect an increased prevalence of associated severe ocular complications later in life.
The identification of an effective and practical treatment will have a significant public health impact on the quickly growing prevalence of myopia and its attendant problems.
Several interventions to decrease the progression of myopia have been proposed and investigated. These include devices that alter the perception of the visual environment and pharmacological treatments. There is no conclusive evidence thus far that any alteration of the pattern of spectacle wear, bifocals, standard contact lenses, or the use of ocular hypotensives effectively retard the progression of myopia.
More recently, efforts have been underway on two fronts to develop and commercialize contact lenses with specific designs to address the peripheral retinal defocus implicated as a factor in the progression of myopia. One is the use of orthokeratology lenses, currently approved for the temporary correction of myopia by flattening the front of the eye, and worn by a very small number of patients to temporarily correct myopia during the day by reshaping the front of the eye after overnight wear of the lenses. It has also been shown that myopia progression seems to be retarded with the use of such lenses. However, this expensive process involves rigid lenses that must be worn overnight, at an increased risk of infection. The optimal optical properties have yet to be worked out as far as controlling the myopia progression in a given patient with a given prescription, as each will likely be a custom-made lens. As these are not approved by the FDA for treating myopia progression, prescribing them as such is off-label, presenting greater risk for the patient and the practitioner who prescribes them as lenses to sleep in for years. There is also some evidence that treating the lower levels of myopia with orthokeratology, up to −2.00 diopters, can actually increase the rate of myopia progression. This is precisely the population that is the desired target of myopia progression control, with the goal of stopping or slowing the condition as early as possible.
The other area of development of lenses that do not reshape the eye, but are designed with various optical features in their peripheries to theoretically affect the associated peripheral retinal imaging and thereby reduce the progression of myopia. These tend to be soft lenses, and are similar to commercially available soft bifocal or multifocal contact lenses, and any distinguishing treatment effects or improved efficacy of these proprietary designs have yet to be demonstrated sufficiently. These devices also suffer from inexact knowledge of specific effective parameters, such as the most effective size or strength of the varied power zones of the lens. The sources of this issue are the unknown effects of exact parameter changes, and the assumption that these zones could be projected directly to the purported treatment area of the retina. The fact is that the lenses must sit on the cornea, so that the different specific lens optical areas do not actually correspond, or project, directly to the desired peripheral defocus areas on the retina. Being at the plane of the cornea, the lenses do not sit at the entrance pupil of the eye and therefore do not optically project their different zones directly to the presumed areas of treatment on the retina. These lenses are intended to be worn virtually all day, every day, which of course not all patients will be able to do for a number of reasons, such as allergies, dryness and discomfort symptoms, and lifestyle activities.
The soft bifocal and multifocal contact lenses also blur the distance vision, due to the constant presence of the near prescription powers in front of the pupil, and blur the near vision, due to the constant presence of the distance prescription power in front of the pupil simultaneously. Unlike bifocal or progressive multifocal eyeglasses, therefore, the patient is constantly looking through the “other” prescription as well as the one they need at the moment, resulting in glare and ghosting at distance from the near prescription, and decreased clarity at near, from the presence of the distance prescription. This is the primary reason for the limited penetration of such products into the market of seventy-plus million presbyopes in the U.S. who do not want to use bifocal glasses or “readers” that they are so dependent on. And the limited patient acceptance of such soft contact lenses has been unpredictably random, resulting in disappointing adoption and use of these lenses, both by the patients and by the people fitting them. The clinical reality is that the vast majority of even those patients who do accept this wearing modality end up wearing lenses that are “pushed” a little, for better distance vision in one eye and better near vision in the other. This could not logically be done in treating myopia, as one would not want to undertreat one eye by giving a less than optimal treatment optical system. The resulting blur of having the full “bifocal” effect in front of both eyes, most likely more symptomatic at distance, would make the wearing of such bifocal lenses even less accepted, especially among children, than it is already in the over-forty presbyopic patient population. The low historical success rate of fitting such lenses and the chair time used up doing so, will continue to limit their adoption by most fitters.
Driving the efforts of most of the proposed pharmacological treatments has been the long-perceived association between excessive near work and myopia progression. Pharmaceutical agents directed at inhibiting the focusing mechanism of the eye (cycloplegic agents) attempt to block near focus by paralyzing the accommodation, or focusing, ability of the eye. Muscarinic antagonists, predominantly atropine, have been available for a century for very temporary application to the eye, such as for dilating the eye for examination of the interior of the eye or for short term inhibition of inflammation of the iris (tissue that forms the pupil) following ocular trauma, or for paralyzing accommodation, the ability of the eye to focus up close. This paralysis allows a more objective determination of refractive error without the focusing mechanism (accommodation) being active. The intuitive and conventional wisdom connecting excessive near work and accommodation to the development and progression of myopia has led to several randomized clinical trials investigating this application of historically established clinical doses of atropine to treat myopia by causing cycloplegia. These studies have demonstrated that the rate of progression of myopia is indeed lower in children given atropine eye drops than those given placebo.
In fact, this substantial proportional reduction in the progression of the myopia condition compares quite well with the pharmaceutical treatment of other chronic progressive diseases. The historically clinically used drop concentrations of 0.5% and 1.0% have been shown to be more effective than experimental lower doses of 0.05%, 0.1% and 0.25%, yielding 0.2 or less diopters/year myopia progression vs. 2-4 times that amount of progression occurring with the use of the lower doses. And appropriately, while many approved drugs have been studied far more in adults than children, in the case of myopia, a condition needing treatment in childhood, studies with atropine have focused on treating children in their study populations. This is important, as children are particularly vulnerable to the systemic and local side effects of higher doses of these agents. These efforts and results using drop delivery have pointed to the need to deliver the pharmaceutical agent at an effective dose without causing excessive side effects to which children are prone.
In fact, most comparative and review studies, including a thorough meta-analysis of randomized controlled trials, have showed that such pharmacological treatment of myopia progression has the greatest efficacy of various treatments tried, including treatments using special eyeglasses and contact lenses.
However, these clinical doses of atropine eye drops lead to pupil dilation and cycloplegia levels that render long-term treatment unacceptable to patients and practitioners. When applied to the long-term treatment of myopia patients, it is not desirable to have a markedly dilated or fixed pupil, nor is it desirable to completely inhibit the focusing ability of the patient. There is a need to maintain a steady-state of functioning pupil and focusing mechanisms, without large fluctuations in function that would create annoying symptoms for the patient. Eye drop application, at whatever dose, affects both the pupil and focusing function variably over time, in a peak-trough fashion, with maximal effect shortly after drop application that slowly decreases towards zero, until the next drop application. Generally for ocular drops these effects wear off in hours or a day, leading to common prescriptions of various eye drops to be used one to a few times a day. With atropine and other anti-muscarinic agents however, one drop can yield dilation that last several days or even a week or more. Therefore progressively lower doses have been subsequently tried for myopia progression treatment due to the debilitating and unacceptable side effects of standard clinical doses for long-term treatment. In recognition of the need for less severe cycloplegia and pupil dilation, prior art teaches the use of low concentration eye drops (200610072954.9 CN 101049287 A, and Chua et al WO2012161655 A1, 2012).
However, topically instilled eye drops are rapidly diluted by tears and quickly washed away from the ocular surface, draining through the puncta. Consequently, an administered drug solution has only a brief opportunity, via a concentration gradient, to deliver drug through the cornea and sclera to the target tissue; in general, the lower the concentration of an applied drug solution, the less chance of delivering sufficient drug to be effective.
It is for these reasons that an anti-muscarinic eye drop solution can only deliver about 5% of their active to the eye. The remaining 95% may be bioavailable to cause systemic effects. Consequently, high concentration anti-muscarinic solutions may result in both local and systemic adverse effects, while low concentration formulations, may generate an insufficient concentration gradient, on the ocular surface, to deliver an effective level of drug to targeted tissue.
A more recently proposed effect of these anti-muscarinic agents relates to slowing the abnormal growth of the eyeball that occurs proportionally to the increasing myopia, as measured clinically by increased axial length of the eye. A number of researchers have proposed that receptors responsible for slowing the abnormal growth of the eyeball are in the posterior ocular tissue near or at the retina, while different receptors, acting to dilate of the pupil and the paralyze accommodation, are in anterior tissues at the ciliary body. If, as proposed, receptors are different, both in structure and in location, that would allow some drugs to act more selectively to suppress myopia progression [e.g. select anti-muscarinics, dopamine agonists, adenosine agonists] while minimally acting to dilate the pupil and paralyze accommodation. Furthermore, it follows that the topical application of a myopia-suppressing drug, if dosed appropriately, may minimize or avoid paralysis of the accommodative system while controlling myopia progression, producing a tolerable and safe treatment.
Unfortunately, with current therapy using atropine eye drops, lowering the drop concentration to reduce the cycloplegia also results in less drug delivery further back in the eye as well. So while the putative treatment effect is independent of cycloplegia, the delivery of the drug using eye drops is not. Lowering the concentration of a topical drug solution, in order to decrease cycloplegia and excessive pupillary dilation, also lowers the concentration of drug that might reach the retina. Therefore, it is not helpful for myopia control if the drug is no longer attaining effective concentration at the tissues that control myopia progression. Without continuous delivery of a low concentration of drug to the surface of the eye, the topical application of an atropine eye drop has insufficient time and drug concentration to deliver the drug to posterior receptors and optimally inhibit abnormal growth of the eyeball. The resulting clinical situation for treatment with atropine eye drops is a peak-trough drug concentration that cannot deliver a steady, highly-effective, yet tolerable, dose into the eye for myopia progression control. Because atropine has a narrow therapeutic window, daily application of eye drops is a highly variable process which may result in frequent days of under-treatment or frequent occurrences of a lasting fixed dilated pupil.
With administration via eye drops, the actual concentration of drug in the drops is not directly dictated by the pharmacodynamics, or the duration and magnitude of response at the active site. The primary determinant is the high concentration gradient of drug necessary at the ocular surface at the time of application of the drop in order to drive the drug into the eye during the short time of exposure to the delivery mechanism, before the entire drop is blinked away and what drug remains is diluted by tears. Since each drop is only present on the eye for a very short time, typically 5% or less of the drug gets into the eye from drop application, and the other 95% either spills out of the eye or gets washed down the tear drainage pathway into the nose and throat, leading to systemic absorption and, potentially, systemic side effects. With topical ocular delivery of myopia-suppressing drugs, therefore, the concentration of drug in the formulation may be far in excess of the amount of drug needed at the targeted receptors but, the exposure of the drug formulation to ocular tears and drainage dilutes the formulation and the drug is rapidly flushed away; drug exposure to the ocular surface is very brief, compared to the duration of treatment desired. Consequently, topical eye drop treatment is generally a very poor way to drive drug to posterior tissues.
That is one of the reasons macular degeneration and other back-of-the-eye diseases have as their main treatment option frequent ocular injections or surgically implanted intravitreal devices. Attempts to drive drug to the retina using drop delivery may result in excessive drug accumulation in the anterior eye tissues. In the case of atropine, this would result in unacceptable side effects of an excessively dilated pupil, limited pupil function, and inability to focus up close.
Unfortunately, the higher doses of atropine, while effective at controlling myopia progression, are associated with the substantial adverse reactions of photophobia and glare, resulting from the large fixed pupil, the inability to focus to see up close (cycloplegia), and recurrent allergic blepharitis (inflammation of the eyelids). These side effects limit the practicality of chronic treatment and hinder the adherence to therapy when using these agents applied via eye drops. Additionally, the higher doses are associated with the most substantial rebound of myopia upon cessation of treatment. Furthermore, severe long-term side effects of light induced retinal damage and cataract formation, primarily due to the more dilated pupil, are expected with the higher doses. The use of lower concentration drops has been tried in attempts to reduce these unacceptable side effects. However, it has been found that the reduction in side effects is accompanied by a corresponding reduction in efficacy for myopia control. That is not because the myopia progression reduction treatment effect is a result of the dilation of the pupil and/or the paralysis of accommodation, which occur towards the front of the inside of the eye, but simply because less drug is penetrating into the back of eye to the targeted receptors, most likely at the retina. Nevertheless, one encouraging finding is that the lower-dose treatments result in less rebound myopia progression following cessation of treatment, improving its net relative efficacy vs. standard drop doses. Patent applications have been made to provide smaller amounts of drug, including low concentration atropine solution, to Wu et al, although they do not specify the frequency of dosing necessary for their invention to be effective (US Pat Appl 20070254914 A1).
It is understood that any eye drop therapy, regardless of the concentration of the active agent in the drop, inherently includes the peak-trough delivery of eye drop instillation regimens and does not provide sustained release of a steady dose of drug to the eye. In fact, the use of drops, at any concentration, requires an excessive amount of drug in the drop relative to what actually penetrates the eye in the short time of exposure to the ocular surface. And most of the drop washes out of the eye because its volume is many times that of the tear film. The result of such washout, blinking and squeezing the eyes shut results in highly variable dosing during application. Adding to that variability is the high variability introduced by the lack of compliance with drop installation, either by missing the eye, dropping in more than one drop at a time, or forgetting to take them and missing the dosing altogether. Such variable application results in an uneven rate of peak-trough drug delivery inherent to the cyclical nature of periodic, highly variable drop applications, with long gaps of absolutely no drug delivery in between doses. While Wu et al teach to lowering drop concentration to limit the side effects of photophobia and focusing difficulties experienced with the high dose drops, the treatment regimen remains an intermittent one based on its eye drop therapy regimen. They do not teach a novel treatment approach, but simply to decrease the strength of the same treatment to a tolerable level, while sacrificing treatment efficacy.
Another approach to reduce such side effects has been to try other, more selective anti-muscarinic agents such as pirenzepine; pirenzepine is a selective M1 blocking agent and consequently, is less active at the muscarinic receptors of the pupil and ciliary body than atropine. Thus it does not dilate the pupil and cause light sensitivity nor loss of ability to focus as much as atropine, and should result in less potential long-term light-induced damage to the retina. Other novel anti-muscarinic compounds have been proposed in recognition of the desire to limit activity at the muscarinic receptors of the pupil and ciliary body while more selectively blocking specific receptor subtypes for the treatment of myopia progression. The use of such anti-muscarinic agents in the drug delivery system described in the Detailed Description of the Certain Embodiments of this invention also fall under the scope of this patent application.
In addition to anti-muscarinic agents, two other classes of drugs have shown promise in the suppression of myopia progression: dopaminergic agents and adenosine agonists.
Dopamine agents, such as dopamine agonists, apomorphine, bromocriptine, quinpirole and levodopa have been shown, in animal models, to retard myopia progression and this class offers another drug class to potentially treat this malady.
In a clinical trial with 68 myopic children, the adenosine agonist, 7-methylxanthine has been shown to reduce eye elongation and myopia progression in childhood myopia. The treatment appears to be safe and without side effects.
In a pilot placebo-controlled clinical trial, an oral dose of 400 mg of 7-methylxanthine was given to 68 myopic children. The study showed that the drug can reduce eye elongation and myopia progression in childhood myopia, with no reported adverse effects. Clearly, systemic treatment with 7-methylxanthine appears to have some effect in retarding axial elongation and myopia progression among myopic children, but these results indicate that perhaps larger doses should be tried. However, in future much-larger trials, required for regulatory approval, treating children orally, with an adenosine agonist, is likely to display some serious systemic effects in children; adenosine receptors play roles in heart regulation, in coronary blood flow and in the brain. Consequently, we anticipate a need for topical ocular delivery. The proposed device herein would eliminate or, at the very least, limit the systemic effects of adenosine agonists. Moreover, it would provide a means to assure better patient compliance. For example, a 7-methylxanthine-loaded device, where this basic drug would be complexed to a fixed acid within the polymer matrix, the drug would be mobile and therefore, would be expected to provide a topical dose to the surface of the eye over a period of weeks or months.
Regardless of drug used or drug class, it is especially important to reduce these side effects in the case of treating myopia, since the younger children, as well as those with more myopia at baseline, are the ones found to have the highest risk for progression. The same study showed that another risk factor for progression was both parents being myopic, which would be a known risk factor at the birth of the child. All indications are therefore for treatment earlier rather than later in life. Consequently, the safest treatments with minimal ocular and systemic side effects would be preferred, enabling treatment at as young an age as possible, at the first sign of myopia, commonly as early as six or eight years old, while minimizing risk to the health of the eye later in life.
While a fully dilated pupil and cycloplegia have been indeed the intended effects of standard clinical drop doses of these drugs for over a hundred years, bluntly achieving the overwhelming dilation and paralysis of focus desired for a few days or weeks, the finding that these drugs can slow the progression of myopia presents a new opportunity to apply these drugs to the eye, but in a manner that requires a far more refined delivery method than eye drops. The improved delivery is needed in order to provide long term chronic dosing with drug to the inner tissues of the eye, while simultaneously avoiding the effects traditionally and purposely achieved with the drops. The original treatment effects of the drops have thus become unwanted side effects. The pupil must remain functioning during the course of treatment for the comfort and safety of the patient, and the patients, especially the young patients that would be targeted with such treatment, must be able to change focus of their eyes. Otherwise, as has been shown, the patients will not tolerate or comply with the treatment and the doctors would not prescribe it due to the risks to the health of the eye from a constantly dilated pupil.
There exists a need therefore, to deliver the drug efficiently to the retina, the tissue where the local effect is postulated to occur, while not excessively building up drug levels more anterior in the eye, closer to the source of overwhelming periodic drop concentrations, and causing, through action in those more anterior tissues, the unwanted side effects of excessive pupil dilation and accommodative paralysis. Current eye drop technology cannot achieve this sustained, micro-dose delivery.
A number of attempts have been made to modify eye drop formulations to keep drug at the surface of the eye for more than a few minutes, to prolong its delivery into the eye It therefore is not surprising that one focus of scientists and clinicians has been on modifying lower dose atropine solutions to extend residence time of the formulation on the ocular surface. One example can be found in Lee et al, U.S. Pat. No. 5,814,638, 1998. Lee et al recognized that for the purpose of inhibiting the abnormal axial growth of the eye in myopia, it is desirable to maximize the delivery of a therapeutic agent to the vitreous humour and retina, while minimizing systemic absorption of the agent to prevent possible systemic side effects. They also remind us that ocular absorption of a therapeutic agent into the posterior chamber of the eye, as opposed to its systemic absorption, depends not only on the relevant ocular anatomy and physiology, but also on the physicochemical property of the agent and the form of the ophthalmic formulation. Their formulation discussions were confined entirely to eye drop formulations, teaching towards the improvement of in vitro physical stability and solubility, and also to the improvement of in vivo therapeutic efficacy by maximizing ocular absorption, while minimizing systemic absorption. They go on to describe the prior art of extending eye drop residence time at the surface of the eye and its effects on tissue and plasma drug levels vs. standard eye drops. Neither the described approach, nor their specific invention, that of prolonging the residence time of an eye drop, however, teach away from very periodic applications of necessarily large amounts of drug in relation to what is needed at the active site.
All of these efforts to prolong residence time of drops at the ocular surface provide a minimal widening of the peaks of the peak-trough pattern of dosing drug, but are not truly sustained low dose delivery.
Additionally, the application of a clinically practical drop of any concentration involves a volume far greater than that of the total amount of tears on the surface of the eye, and invariably overwhelms the tear film and flows out of the eye and systemically through the tear drainage and the nose and throat. It would be difficult, therefore, even given a prolonged drop formulation, to provide an adequately controlled, low variability, sustained delivery rate of drug to the ocular tissues with eye drop therapy. This mode of delivery cannot provide the restricted range of an anti-muscarinic drug needed to balance efficacy and tolerable side effects, on a consistent basis during long term therapy. And, while the clinical use of dopamine or adenosine agonists lag significantly behind the use of anti-muscarinic agents, a similar need for an adequately controlled, sustained delivery rate of drug can be anticipated, in order to minimize local and systemic adverse effects and improve patient compliance.
With proposed anti-muscarinic ocular therapies for myopia progression, there is a clear need to deliver small enough doses to avoid side effects from the enlarged pupil and the inability to see up close, while getting enough drug into the eye, particularly to the retina and choroid, for adequate efficacy. Likewise, we anticipate a clear need to deliver sustained small doses for other drug classes, in order to deliver drug posteriorly, while avoiding local and systemic adverse effects.
In general, it is difficult to get a drug to penetrate the eye from the bloodstream; systemic doses (oral, IV, IM, etc.) of a drug require a high-enough concentration to get the drug through the blood-retina barrier. Systemic administration of a drug potentially exposes the patient to serious systemic adverse effects. Therefore, the vast majority of drug administration to the eye for a long time has been in the form of eye drops, and more recently, for treatment at the back of the eye, in the form of far more invasive direct, repeated injections or surgical implantation of a drug delivery device. Eye drops must be loaded with excessive drug quantities than is required at the site of treatment inside the eye, in order to drive the drug into the eye during the short time the drop is at the surface of the eye. This excess drug is often the source of the undesirable ocular and systemic side effects experienced. As with many chronic ocular conditions, such as glaucoma, inflammation, infection and degenerations, the prior art and science have led the field to conclude that low dose, sustained drug delivery is aspired to as the ideal method of treating most chronic ocular conditions. And the only non-invasive way to get low dose drug into the eye in a sustained rate is to have a source of drug at or near the surface of the eye most or all of the time, in order to maintain a constant concentration gradient of available drug to drive the drug into the eye. This would allow sustained treatment at effective doses at the desired site of action, while avoiding ocular and systemic side effects from the comparatively high concentration loading necessary with drops. While injections, or implantation of a device, under the surface layers or right through into the interior vitreous of the eye provide access of the drug to posterior tissues, these procedures must be repeated several times a year and present significant risk of infection, uveitis, retinal separation, and other serious adverse effects
There clearly exists a need therefore, for a non-invasive low dose, sustained local delivery of myopia-suppressing drugs to the eye for the treatment of myopia progression. Such delivery should achieve maximal clinical efficacy while maintaining accommodation and pupillary function without extended periods of fixed or excessive dilation, rendering it an acceptable treatment to practitioners for its safety profile and to patients for its tolerability. Minimizing the dilation would protect the back of the eye from excessive UV light exposure over the years of treatment. Patients would experience reduced ocular side effects involving photophobia, inability to read, and inflammation of the ocular surface and lids, as well as various potential systemic side effects. A sustained delivery device worn on the eye also would offer the convenience of not having to take drops one or multiple times a day.
The present invention uniquely recognizes the importance of maintaining the dynamic function of the pupil and delivers the drug in a sustained manner, relying on a low rate of low variability delivery continuously over 24 hours a day, rather than simply reducing the concentration of a daily drop regimen. This constant, micro-dose delivery does not overwhelm or even affect the volume of the tear film during drug delivery, and maintains high treatment efficacy, while reducing attendant side effects from historical, experimentally effective drop concentrations that prove intolerable and impractical for clinical use. While the simple approach of a reduction in eye drop concentration has been shown to also reduce the efficacy of the treatment, the present invention aims to deliver drug at effective levels over the entire day and night, constantly driving it into the tissues at the back of the eye. Such constant, micro-dose delivery will not overload the receptors of the more anterior tissues at any one time and create undesirable side effects, but rather continuously deliver the drug to the internal eye to maintain adequate levels at the retina to continuously retard the progression of myopia.
Contact lenses have been proposed to deliver various drugs to duplicate the effects of drops, such as cycloplegia induced by atropine to treat myopia (U.S. Appl. 20140036225 to Chehab). But current contact lenses, and to our knowledge modified contact lens materials under development—none being currently available commercially—including those with the addition of liposomes, nanoparticles, molecular imprinting or incorporated films, all have stated goals of attaining clinical treatment comparable to current approved drops, and no case has been made for new treatment approaches involving ultra-low, in the range of micrograms or less per day, sustained dosing of current medications as is the case of the present invention. Furthermore, the overall shapes of contact lens designs are not favorable for extended periods of drug release as they are uniformly thin. The lenses consequently release drug too quickly, not having the bulk areas in their shape to enable long term drug diffusion and release at consistent very low doses.
The lenses consequently release drug too quickly, not having the bulk areas in their shape to enable long term drug diffusion and release at consistent very low doses.
In U.S. Appl. 20140036225 Chehab describes a contact lens with myopia control optics that also contains a muscarinic blocking agent. The incorporation of the muscarinic blocking agent into the contact lens is performed after the lens is manufactured by dissolving the agent in a solvent and placing the lens in that solvent for a period of time. The agent diffuses into the polymer matrix until equilibrium concentration is reached. The final concentration of agent in the lens is governed by the partition coefficient of the system. At that point the solvent is removed and the lens packaged, presumably in a drug solution to prevent elution during storage and shipment. Due to the limitations of such a system, the drug comes out fairly quickly once the lens is placed on the eye, and it is stated in that application that 80% loss is expected, so that the amount delivered from the device is measured as milligrams per day.
Contact lens delivery systems are intuitively appealing, and hence have been proposed for decades, and activity continues on those efforts. But conventional contact lenses cannot deliver drug for very long and there are several disadvantages to delivering a drug using a contact lens. The dimensions of the lens, choice of material and material chemistry available in contact lenses are all quite limiting. This is due to the restrictive necessities of covering the pupil but remaining very thin for comfort, having substantial proportional material and water phases, being optically clear and finished, and being highly oxygen permeable. As a result, a limited amount of drug can be incorporated into a conventional contact lens (typically only the water phase), and it all comes out of the lens very quickly, as it is all near a surface to start with. The basic lens material chemistry cannot be specifically tailored to any useful degree to the chemistry of the drug in order to optimize solubility, uptake and release kinetics without adulterating the necessary oxygen permeability and optical qualities. Oxygen permeability is a critical property of any device that will cover the cornea for any substantial proportion of the day or night. Without it the cornea cannot function and becomes more vulnerable to invasive blood vessels and blinding infections. Optical quality and clarity are necessary for the wearer to be able to see through the device. Any material or structural modifications to overcome these limitations of oxygen permeability and optical quality very quickly result in an extensively engineered and expensive contact lens, possibly rendered unwearable by most people, and/or unwearable on any extended wear (overnight) basis, for drug delivery. In spite of sophisticated modifications much of the drug, 40-90%, comes out in the first one to three days. Therefore, such as system could not work for myopia control progression with a drug such as atropine. Loading adequate drug to deliver a sustained dose over several days, weeks or months that would adequately control myopia progression would lead to a relatively large initial burst. As a result, too much drug would come out initially, leading to an excessively dilated pupil for several days, even after the level of release had decreased. This would be more akin to the peak/trough eye drop delivery, but once every few days instead of daily, than to a narrowly controlled range of sustained, low dose delivery for weeks or months. Mitigating this initial burst would require a preconditioning step of a few days in buffer to elute out the unwanted initial burst of drug, as suggested by prior art literature. Such a procedure would have regulatory and practical complications, as it could be difficult to coincide with the patient's dispensing visit and would have to be done using a sterile procedure or in a solution with substantial preservatives or disinfection agents that would minimize microbial growth.
It should be noted that most people are not able to sleep in contact lenses even when the lenses are designed optimally for such use, irrespective of any additional material or engineering requirements introduced for drug delivery. In fact, a significant portion of the population of successful daily wear contact lens wear patients are not able to wear their contact lenses even all waking hours every day, for a variety of reasons related to activities, environment, dryness and discomfort. That is one of the reasons there are so many different lens materials, with varying moduli and comfort sensations. Daily removal of drug-releasing lenses requires cleaning, rinsing and overnight disinfecting solutions, and would result in variable drug loss due to the drug release into the solutions. Daily disposable lenses would have to be packaged, or potentially rehydrated, in solutions that would also have to be modified to prevent drug loss from the lens. These solution requirements complicate the care and storage regimen and the regulatory approval, and increase development costs and expense of the use of the end product. And of course, if various polymers were produced to increase the number of comfortable wearers, each drug delivery material would require separate regulatory approval.
Due to the challenges of incorporating drug into a contact lens type device for sustained delivery, various other topical devices and implants have been developed for sustained drug delivery to the eye. Similar to the contact lens approach, that is to say, taking a device that has a history of being tolerated in the eye by a reasonable proportion of patients, punctual plugs, originally used to treat dry eye by blocking or partially blocking the drainage of the liquid tears from the eye, have been the subject of attempts to adapt them to drug delivery. Loading drug into various materials that are configured to fit into the tear drainage tissue openings has led to some limited clinical trial success but no marketed products to date. Their most significant limitations are issues with accidental and potentially undetected ejection, excessive tears, canaliculitis, and difficulties loading enough drug into these necessarily tiny devices to achieve clinically effective drug release over time, as they must be replaced when they run out of drug, requiring a visit to the doctor's office.
Other approaches to sustained delivery devices involve those with sizes and shapes predicated on the art of tablet manufacture and the desire to be inconspicuous in situ. That is, comfort and retention in the conjunctival sac is attained by slipping a device of simple manufacture, and usually of unspecified material, into the pocket formed by the conjunctiva lining the eyeball and the inside of the eyelid, and presuming it would be tolerated by the subject by virtue of its small size. This lack of design specific to the limiting contours of the intended space leads to discomfort and too-frequent ejection of devices of any significant volume, and few of these devices were developed as far as clinical investigation. This limitation of overall dimensions in turn again significantly restricts the amount of drug they are able to contain and consequently deliver. Nevertheless, efforts continue in this field in response to the recognized need. An example of a device large enough to carry substantial drug for sustained release, yet has dimensions to fit comfortably and with stability in that conjunctival sac, is Leahy et al, 2012.
An example of a commercially produced ocular insert for sustained drug delivery is found in the subject of U.S. Pat. No. 3,618,604, the Ocusert®, assigned to Alza Corporation. This product was designed from an engineering standpoint of making a drug-releasing “sandwich”. Adequate retention and comfort were presumed by virtue of its small size. Several subsequent patents assigned to Alza Corporation (U.S. Pat. Nos. 3,416,530, 3,828,777) also describe devices that are designed to improve drug delivery kinetics based primarily on material characteristics. These patents utilize a simple design for devices that are “adapted for insertion in the cul-de-sac of the conjunctiva between the sclera of the eyeball and the lower lid, to be held in place against the eyeball by the pressure of the lid”. This prior art is an example of using sustained release from their material chemistry to replace eye drop therapy, in order to minimize the effects focusing ability while maintain the drugs desired clinical effect inside the eye, which happened to be intraocular pressure reduction. The drug they used, pilocarpine, was marketed for treatment of glaucoma under the tradename, Ocusert®. Ocusert® had practical advantages (similar to the proposed device herein) of delivering a continuous low-concentration topical dose, in order to reduce side effects, while maintaining efficacy; when compared to pilocarpine topical drops, in that it demonstrated reduced drug side effects, such as excessive focusing and pupil constriction. (Note, however, that these side effects are the opposite from the side effects of anti-muscarinic drugs, which our device is designed to reduce or eliminate). Ocusert® was able to deliver a continuous effective dose for a week or two, with a single administration. However, significant problems in retention and irritation with the use of the Ocusert® devices are reported in the literature. In fact, for those reasons and because pilocarpine is now lower on the list of preferred pressure lowering agents, the products have been discontinued.
An important teaching from this prior art is that it demonstrates, at least for a couple of weeks, that a device can deliver a low dose to the surface of the eye in a sustained manner and maintain efficacy, while substantially reducing undesirable pupil and focusing side effects that is typically seen with the corresponding eye drop administration. Such delivery exceeds the capabilities of even state-of-the-art repeated daily eye drop therapy. The subject invention, herein, also reduces pupil and focusing side effects (opposite to those of pilocarpine reduced by the Ocusert®'s delivery) while maintaining a desired clinical effect, but presents a more sophisticated matrix that can deliver a tighter range of drug release over the course of treatment, and for more than twice the treatment time of that prior art. And, in addition, this device can shaped to the surface of the sclera, so that the retention and irritation problems, as seen with the use of the Ocusert® device, are eliminated.
The prior art on noninvasive ocular device drug delivery, whether through the adaptation of contact lenses or punctual plug devices, or through devices developed de novo specifically for drug delivery, thus teaches attempts to present drug at the front of the eye for sustained release, in order to mimic and improve upon the recognized clinical treatment effects of, and replace the use of, currently available eye drops, for their current disease treatment applications. Many of these device patents and applications are proposed as platform technologies, claiming sustained release of a wide range of potential candidate drugs based on their historical use in eye drop treatment regimens. They seek the same clinical treatment effects, while perhaps reducing known side effects somewhat. They do not, however, specify a material chemistry and device that would deliver these drugs in a way to provide any specific therapy option not available with drops.
More specifically, the prior art, for topical ocular drug delivery devices does not teach ways to design a device with a polymer matrix that will continuously deliver drug to the surface of the eye, at a sufficient concentration to transport drug to receptors in posterior ocular tissues, while presenting a low enough concentration (a “micro dose”) anteriorly, to minimize undesirable side effects triggered by receptors in anterior tissues. The art recognizes that attempting to get drug deeper into the eye with eye drops briefly and necessarily overwhelms the front of the eye with drug in order to drive drug into the eye, causing side effects. Immediately subsequent to that, when the drop has washed out of the tear film after a few minutes, there is little remaining impetus to continue to drive drug diffusion further into the eye. The art has focused, rather, on trying to get enough drug into the eye to the same target tissues as the drops, simply to mimic or enhance the same mechanism of action and treatment efficacy of the drug in eye drops, while avoiding the necessity of applying the eye drops.
Not everyone's pupil is the same size in the same light conditions, and everyone's pupils normally change size according to ambient light conditions, constricting in brighter conditions and dilating in darker conditions, working much like a camera's aperture. But no one is comfortable with an excessively dilated or fixed, dilated pupil. The pupil must be able to constrict to increased light and dilate in response to a decreased ambient light level. That is its function and it must be maintained for patient comfort and vision in various light levels. It needs the ability to have a relative size change under changing light conditions in order for the individual to be comfortable. The absolute size is a factor but not the critical factor. A group of people together in a given ambient light level environment can have a variety of different pupil sizes (within limits) and yet all be quite comfortable. It is the ability to change size in changing light that must be maintained.
The retina needs to function effectively over an extremely large range of sensitivity. The range from dark threshold to a light level that can possibly cause damage covers a luminance range of about 14 log units. This is a range of 1:100,000,000,000,000. At the lower end of this range the visual system trades color perception and good visual acuity for very high sensitivity to low light levels. The eyes take time to adjust to different light levels, and the dynamic range of the human eye in a given scene can actually be quite limited due to optical glare. The pupil plays a critical role in regulating and adjusting to light levels that reach the retina by giving it a chance to adapt to changing levels as well as regulating the total amount of light reaching the retina at a given time. This is especially true at the ranges where proportional response of the rod and cone photoreceptors change, on either end of the mesopic range. For example, in slightly brighter conditions than that, as the photopic range is entered, rod saturation begins and the rods output no longer increases as luminance increases. They are already responding as vigorously as they can. A pupil that can constrict normally on increased light helps the retina respond more comfortably to this increased brightness. And of course when the total light and its energy is high enough, such as in the case of an excessively dilated pupil it can cause retinal damage. The lower dose atropine drop studies reported that the children easily tolerated 1 mm larger pupils than they normally have under normal light conditions, with very few (6%) in that study group (vs.>60% in the higher dose groups) asking for tinted glasses, demonstrating that an increased pupil size vs. an individual's “normal” size is well tolerated, as long as it is not too excessive. The normal drop dose studies demonstrated that a very large, fixed pupil is not tolerated well at all. Nor is it considered safe over the long term, due to the likely excessive exposure to UV light to the internal eye. The lower doses also did not cause the children to be unable to read as occurred with the standard drops. In fact, despite some mild glare symptoms in a study with 0.01% drops, there was no decrease in visual acuity, quality of life or reading speed. And of course routine eye exams demonstrate that even an hour or two of excessively large and unresponsive pupils and inhibited focusing is disliked by most patients who must try to function normally, such as driving or working, after they leave the appointment.
To counteract the growing hours of intense near focus during the day, including studying and what is often referred to as “screen time”, it is recognized in the field that the proposed optical treatments described above would be expected to be more effective if they are extended throughout the waking hours. And in the case of a pharmaceutical potentially affecting the continuing growth of the eye, it is recognized that it would be preferred to provide a sustained release system to deliver small amounts of drug steadily over the course of the day and night. It is also recognized in the field that the drug cannot interfere substantially with the ability of the patient to perform those very same intense near focusing activities, either by the ocular side effects of fixed and dilated or excessively dilated pupils, or by limiting the ability to focus up close (cycloplegia). Such side effects have been demonstrated to be intolerable and cause drop out from the treatment regiments with the 1.0% atropine drops, for example. Additionally, it would be unacceptable to expose the eye to excessive ultraviolet light rays through a fully dilated pupil all day, over several years of treatment of the myopia, only to expect an increased complications of retinal toxicity, early cataract and macular degeneration later in life.
With atropine and other anti-muscarinic agents, the maximally dilated pupil and inability to constrict in increased levels of ambient light is achieved with standard atropine eye drop dosing, which historically have been used for purposeful complete dilation for ocular examination or for acute, not longstanding, treatments of inflammation. Consequently, such treatment is associated with the expected, unacceptable levels of light sensitivity, increased UV exposure and visual blur for several days, often after a single drop of historical and current clinical eye drop doses.
Despite these side effects, conventional clinical atropine eye drops, in the available doses of 1.0% and at times 0.5%, have been tried for the treatment of myopia progression. The driving thought for this approach was originally intending to affect pharmacologically the same mechanism of action as one of the primary mechanisms of action of the clinical drop dosing, that of cycloplegia, or paralyzing the accommodation, or near focusing ability, of the eye, which had long been proposed, and expressed as “excessive near work”, by scientists and clinicians in the field, as a primary cause of increasing myopia. This line of thought came out of the common observation that patients that tend to perform excessive near work tend to get more nearsighted over time when continuing such near tasks, such as young Jewish men studying the Torah for hours a day, people getting jobs in data entry or other intense computer-use occupations, returning to hours of studying in professional school, etc. While eye doctors could track individual patients thus affected, not all patients are thus affected and proving the effect in large controlled studies has been obfuscated by the disproportionately large influence of genetics. Nevertheless, it remains common perception that excessive near work causes increased or perhaps even the onset of myopia (perhaps in those so predisposed genetically), and the increasing worldwide prevalence of myopia with increased near vision demands associated with increasing urbanization and education, trending to 80-90% of Asian youth today, and 50% of the world's population by 2050, lends credence to what has been apparent to lay and professional observers. This phenomenon is often expressed as the unproven maxim that the more you wear your glasses for myopia correction (glasses for myopia increase the accommodative demand more than not wearing them) and the more near work you do, the more nearsighted you will get. However, subsequent to and in addition to that intuitive proposed mechanism of action, it was shown that anti-muscarinic agents, independent of their effects on pupil dilation and focusing, have the desired effect of reducing the growth of the eyeball as measured by increasing axial length in progressive myopia. These effects take place further back in the eye, likely at the dopamine receptors of the retina. And eye drops do not deliver drug to the retina effectively, especially when their concentration must be reduced to avoid the side effects on the pupil and focusing that occur more toward the front of the eye where the drops are applied. Currently approved myopia treatment does not exist, but the off-label use of low concentration drops, such as 0.1% or 0.01% is occurring more in certain countries, reflecting the recognized need to address this growing problem with an effective and practical treatment.